PI3 kinase/Akt signaling mediates epithelial-mesenchymal transition in hypoxic hepatocellular carcinoma cells

Biochem Biophys Res Commun. 2009 May 8;382(3):631-6. doi: 10.1016/j.bbrc.2009.03.088. Epub 2009 Mar 20.


Hypoxia activates genetic programs that facilitate cell survival; however, in cancer, it may promote invasion and metastasis. Although the exact mechanisms driving hypoxia-induced invasion and metastasis remain elusive, we hypothesized that epithelial-mesenchymal transition (EMT) may play a major role. We investigated this in vitro by treating hepatocellular carcinoma cells under 1.0% O(2). After the hypoxia treatment, the cells exhibited some morphological changes including cell elongation, cytoskeletal rearrangement, and junctional disruption. Moreover, expression of the epithelia-specific marker E-cadherin was decreased and expression of the myofibroblast-specific marker vimentin was detected in the treated cells. Cell migration and ECM gel invasion were increased. These findings were consistent with events observed during EMT. Hypoxia-induced EMT is accompanied by increased phosphorylation, activation of Akt and the downstream signaling. Hypoxia-induced EMT was blocked by PI3K inhibitor LY294002. The results suggest that the PI3K/Akt-dependent signaling pathways serve to regulate hypoxia-induced EMT of hepatocellular carcinoma cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carcinoma, Hepatocellular / enzymology
  • Carcinoma, Hepatocellular / pathology*
  • Cell Hypoxia
  • Chromones / pharmacology
  • Epithelium / enzymology
  • Epithelium / pathology
  • Humans
  • Liver Neoplasms / enzymology
  • Liver Neoplasms / pathology*
  • Mesoderm / enzymology
  • Mesoderm / pathology
  • Morpholines / pharmacology
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Kinase Inhibitors / pharmacology
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors
  • Proto-Oncogene Proteins c-akt / metabolism*


  • Chromones
  • Morpholines
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Kinase Inhibitors
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Proto-Oncogene Proteins c-akt